CD8+ tissue-resident memory T cells are expanded in primary Sjögren’s disease and can be therapeutically targeted by CD103 blockade

Abstract

<p><strong>Objective</strong> Tissue-resident memory cells (Trm) are a subset of T cells residing persistently and long-term within specific tissues that contribute to persistent inflammation and tissue damage. We characterised the phenotype and function of Trm and the role of CD103 in primary Sjogren’s syndrome (pSS).</p><p><strong>Methods</strong> In both pSS and non-pSS sicca syndrome patients, we examined Trm frequency, cytokine production in salivary glands (SG) and peripheral blood (PB). We also analysed Trm-related gene expression in SG biopsies through bulk and single-cell RNA sequencing (scRNAseq). Additionally, we investigated Trm properties in an immunisation-induced animal model of pSS (experimental SS, ESS) mouse model and assessed the effects of Trm inhibition via intraglandular anti-CD103 monoclonal antibody administration.</p><p><strong>Results</strong> Transcriptomic pSS SG showed an upregulation of genes associated with tissue recruitment and long-term survival of Trm cells, confirmed by a higher frequency of CD8⁺CD103⁺CD69⁺ cells in pSS SG, compared with non-specific sialadenitis (nSS). In SG, CD8⁺ CD103⁺ Trm contributed to the secretion of granzyme-B and interferon-γ, CD8⁺ Trm cells were localised within inflammatory infiltrates, where PD1+CD8+ T cells were also increased compared with nSS and MALT lymphoma. scRNAseq of PB and pSS SG T cells confirmed expression of <em>CD69, ITGAE, GZMB, GZMK</em> and <em>HLA-DRB1</em> among CD3⁺CD8⁺ SG T cells. In the SG of ESS, CD8⁺CD69⁺CD103⁺ Trm producing Granzyme B progressively expanded. However, intraglandular blockade of CD103 in ESS reduced Trm, reduced glandular damage and improved salivary flow.</p><p><strong>Conclusions</strong> CD103⁺CD8⁺Trm cells are expanded in the SG of pSS and ESS, participate in tissue inflammation and can be therapeutically targeted.</p>